Variation in the risk for substance use disorder (SUD) results from the interaction of genetic and environmental factors. Molecular genetic studies may help disentangle these factors. Few human genetic polymorphisms, however, have been studied in relation to the liability to SUD. Among these loci, the genes encoding dopamine receptors and monoamine oxidase A (MAOA) attract special attention because of their demonstrated or hypothesized involvement in the risk for substance abuse. Furthermore, our pilot data support an association between polymorphisms at the dopamine D5 receptor and MAOA genes and the risk for SUD. We have the following specific aims: Aim 1. Evaluate known polymorphisms at the dopamine receptor and MAOA genes, separately and as haplotypes, for their association with the liability to substance dependence using family-based methods in 350 families ascertained via an adolescent male with a DSM-IV diagnosis of substance dependence, and population-based methods in both adult case-control male and female samples and adolescent male case-control sample; Aim 2. a) In the family-based sample, determine subjects' haplotypes for each locus using all detected polymorphisms; b) Determine polymorphisms affecting SUD risk using the haplotype data in a measured haplotype analysis; Aim 3. a) Determine the influence of DNA polymorphisms, both at the level of individual loci and considered jointly as haplotypes, on personality characteristics; b) Evaluate the influence of personality characteristics on the association between the liability to substance dependence and the DNA polymorphisms; and Aim 4. Evaluate the effects of environmental factors (e.g., adverse individual life experiences, affiliation with delinquent peers, high environmental crime) on the variation in liability to substance dependence and its relationship with genetic polymorphisms. The proposed research will examine the role of DNA polymorphisms, personality and environmental factors in variation in the liability to SUD. Even though the effects of single genes may be small, their attributable risk may be large because of a high frequency of high-risk-associated alleles in the population. Their combined effect may be substantial. Moreover, the effect of measures of drug abuse prevention that could be developed based on the knowledge of genetic mechanisms contributing into the SUD risk variation in the population may be greater than the "natural" contribution of such mechanisms. The results will allow for more accurate estimation of the risk for SUD and suggest approaches for prevention.